Thyroxine replacement: a clinical endocrinologist’s viewpoint
Abstract
Background: Hypothyroidism affects 2–5% of the general population. Patients with uncorrected disease suffer significant morbidity and have an increased risk of cardiovascular disease and neurocognitive impairment. Levothyroxine, the treatment of choice, is inexpensive, easy to administer and in most cases restores well-being while normalizing thyroid function. However, 30–50% of individuals on levothyroxine are either over-treated or under-treated and others remain dissatisfied with treatment despite achieving thyroid hormone concentrations within the laboratory reference interval. Methods: This review is based on a systematic search of the literature for controlled trials, systematic reviews, guideline papers and cohort studies addressing best practice in thyroid hormone replacement. Results: Recent decades have seen improvements in patient management strategies driven by a better appreciation of levothyroxine pharmacokinetics. However, aspects of therapy such as the optimal timing of medication, strategies to overcome treatment non-adherence and target thyroid stimulating hormone concentrations in pregnancy and in patients with differentiated thyroid cancer remain challenging. Furthermore, there is now a substantial body of literature on common genetic variations in the deiodinases and thyroid hormone transporters and their role in the local regulation of thyroid hormone delivery. The benefits of combination therapy with liothyronine and levothyroxine are uncertain, and while it is theoretically probable that subsets of genetically predisposed individuals will benefit from combination therapy the existing evidence is as yet limited. Conclusion: Despite the availability of thyroid hormone replacement for more than a century, there are still substantial challenges in practice and opportunities to improve treatment outcomes.
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At therapeutic doses, levothyroxine is safe, well-tolerated, with rarely reported serious side effects.
“At therapeutic doses, levothyroxine is safe, well -tolerated, with rarely reported serious side effects. 67”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [67]
Almost half of LT4-treated primary hypothyroid patients worldwide appear under- or over-treated when serum TSH is used as marker.
“Indeed, using serum TSH as a marker of adequate thyroid hormones status in LT4-treated primary hypothyroid patients, almost half of treated patients in the world appear to be under- or over-treated (2).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [2]
Observational studies of LT4-treated patients with hypothyroidism have demonstrated that almost half have serum TSH levels either low or high, indicative of over- or under-replacement.
“Observational studies of LT4-treated patients with hypothyroidism have demonstrated that almost half of the patients have serum TSH levels that are either low or high, indicative of over- or under-replacement (2).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [2]
The long-term safety of Liothyronine has not been established in children.
“Unlike Levothyroxine which has extensive safety data the long-term safety of Liothyronine has not been established in children [53, 54].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [53]
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Global epidemiology of hyperthyroidism and hypothyroidism
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Self-citationGastrointestinal malabsorption of thyroxine
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“Unlike Levothyroxine which has extensive safety data the long-term safety of Liothyronine has not been established in children [53, 54].”
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Precision Medicine in Autoimmune Thyroiditis and Hypothyroidism
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“At therapeutic doses, levothyroxine is safe, well‐tolerated, with rarely reported serious side effects.(67) Levothyroxine has a narrow therapeutic index, however, and both under‐treatment (TSH above the reference range) and over‐ treatment (TSH below the reference range) are common, with cross‐sectional studies consis…”
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“Observational studies of LT4-treated patients with hypothyroidism have demonstrated that almost half of the patients have serum TSH levels that are either low or high, indicative of over-or under-replacement (2).”
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L-T4 Therapy in Enteric Malabsorptive Disorders
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Current challenges in the pharmacological management of thyroid dysfunction in pregnancy
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Self-citationCombination Thyroid Hormone Replacement; Knowns and Unknowns
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Potential of l -thyroxine to differentiate osteoblast-like cells via Angiopoietin1
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Non-thionamide antithyroid drug options in Graves’ hyperthyroidism
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Editorial: Levothyroxine Therapy in Patients With Hypothyroidism
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Over- and undertreatment with levothyroxine—findings of the population-based Rhineland Study
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Decreased expression of ileal thyroid hormone transporters in a hypothyroid patient: a case report
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Liquid L-T4 therapy in hypothyroid patients with gastric diseases, an observational study
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Abram, A. M. D., Volpi, F., Chumbiauca, E., García‐Goñi, M., & Galofré, J. C. (2025) · Endocrinología Diabetes y Nutrición · doi:10.1016/j.endinu.2025.501645 · Cited by 1 · see citing works
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Role of Ayurveda in the Management of Hypothyroidism - A Case Report
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Enhancing levothyroxine dosing accuracy post-total thyroidectomy using body fat percentage
Abram, A. M. D., Volpi, F., Chumbiauca, E., García‐Goñi, M., & Galofré, J. C. (2026) · Endocrinología Diabetes y Nutrición (English ed ) · doi:10.1016/j.endien.2025.501645
Troshina, E., Mazurina, N. V., Botasheva, M. H., Platonova, N. M., Pershina-Milyutina, A. P., & Gasymova, I. R. K. (2026) · Problems of Endocrinology · doi:10.14341/probl13665
Centanni, M., & Virili, C. (2026) · L Endocrinologo · doi:10.1007/s40619-026-01807-0
Noise-Tolerant Multi-Model Ensemble for Robust Hypothyroid Classification
Zacharia, A. J., Trivedi, Y., Chathiwala, Z., Lakdawala, H., Singh, J. K., & Shah, S. (2026) · International Conference on Advancements in Smart, Secure and Intelligent Computing (ASSIC) · doi:10.1109/assic70037.2026.11717313
- Authors
- Eligar, V, Taylor, P., Okosieme, O., Leese, G., & Dayan, C.
- Affiliations
- Cardiff University (GB)
- Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK
- University of Dundee (GB)
- ORCID
- Eligar, V
- Venue
- Annals of Clinical Biochemistry: International Journal of Laboratory Medicine
- Publisher
- SAGE Publications
- Published
- 2016-04-28
- Volume
- 53
- Issue
- 4
- Pages
- 421-433
- ISSN
- 0004-5632 (ISSN-L)
- 1758-1001
- OpenAlex
- W2345078908
- Cited by
- 72
- References
- 118
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 9 · 2021: 11 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 2
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Clinical Biochemistry International Journal of Laboratory Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- American Thyroid Association
- Association for Clinical Biochemistry and Laboratory Medicine
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- levothyroxine, hypothyroidism, thyroid hormone replacement, medication adherence, pregnancy, differentiated thyroid cancer, thyroid hormone transporters, overtreatment and undertreatment
- MeSH terms
- Endocrinologists, Animals, Humans, Hypothyroidism, Thyrotropin, Thyroxine, Randomized Controlled Trials as Topic, Hormone Replacement Therapy
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